Incidence of cancer increases with age. The multiple-hit hypothesis posits that this direct correlation arises from a requirement for multiple genomic mutations before a cell becomes cancerous. In contrast, a direct link has been discovered between aging and genomic instability in the model organism Saccharomyces cerevisiae, a single-celled yeast. The Sir2 protein is limiting for lifespan in yeast, and is important for maintaining genomic integrity. Sir2 enzymatic activity is limited by the abundance of a metabolite called NAD(+), indicating that Sir2 may connect metabolism and aging. A human protein homologous to Sir2, called SIRT1 modulates p53, which is a regulator of cell division and is involved in most types of cancer. This suggests that Sir2 has a conserved role in yeast and human in integrating metabolic signals to regulate genomic stability. A major goal of cancer research is to develop predictive models of cancer risk. By deciphering how Sir2 regulates genomic stability, and how Sir2 is regulated by environmental signals, models may be constructed to predict the influence of dietary and environmental factors on cancer risk. To this end, the proposed research will focus on the characterization of two novel Sir2 interactions in yeast and their biological function.